DNA-release by Streptococcus pneumoniae autolysin LytA induced Krueppel-like factor 4 expression in macrophages

• Published in: Scientific reports Vol. 8; no. 1; pp. 5723 - 14
• Main Authors: Herta, Toni, Bhattacharyya, Aritra, Bollensdorf, Christian, Kabus, Christin, García, Pedro, Suttorp, Norbert, Hippenstiel, Stefan, Zahlten, Janine
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.04.2018; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/21; 13/89; 38/22; 45/77; 631/80/304; 692/699/255/1318; 82/80; Autolysis; Deoxyribonucleic acid; DNA; Humanities and Social Sciences; Immune response; Inflammation; Interferon; Interleukin 10; KLF4 protein; Krueppel-like factor; Macrophages; multidisciplinary; MyD88 protein; Myeloid cells; Phenotypes; Science; Science (multidisciplinary); Streptococcus infections; Streptococcus pneumoniae; Supplements; TLR9 protein; Toll-like receptors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-24152-1

The recruitment of myeloid cells to the lung is of utmost importance for the elimination of invading pathogens. We investigated the Streptococcus pneumoniae -dependent induction mechanism of KLF4 in macrophages as a potential regulator of the macrophage immune response. We demonstrated that only viable pneumococci, which have direct contact to the host cells and release LytA-dependent DNA, induced KLF4. Exogenous supplementation of pneumococcal, other bacterial, eukaryotic foreign (human) or self (mouse) DNA to autolysis-deficient pneumococci restored (at least in part) pneumococci-related KLF4 induction. Experiments using TLR9, TRIF and MyD88 knockout macrophages revealed that TLR9, TRIF and MyD88 were partly involved in the S. pneumoniae -induced KLF4 expression. BMMs missing important DNA receptor related molecules (ASC −/− , STING −/− ) showed no differences in pneumococci-related KLF4 expression. Similar results were observed with IFNAR −/− BMMs and Type I IFN stimulated cells. LyzMcre mediated knockdown of KLF4 in BMMs resulted in a decreased secretion of proinflammatory cytokines and enhanced IL-10 release. In summary, we showed that pneumococci-related KLF4 induction in macrophages is mediated via a PAMP-DAMP induction mechanism involving a hitherto unknown host cell DNA sensor leading to a more proinflammatory macrophage phenotype.